[ CAS No. 89402-42-6 ] {[proInfo.proName]}

Name: 89402-42-6|2,3-Difluoro-5-(trifluoromethyl)pyridine|98%
Brand: Ambeed
SKU: A278142
Price: 6.0 USD
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Quality Control of [ 89402-42-6 ]

COA NMR CNMR HPLC LC-MS

Related Doc. of [ 89402-42-6 ]

SDS Specification

Alternatived Products of [ 89402-42-6 ]

Product Details of [ 89402-42-6 ]

CAS No. :	89402-42-6	MDL No. :	MFCD04972837
Formula :	C₆H₂F₅N	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	XIFCGIKPAAZFFS-UHFFFAOYSA-N
M.W :	183.08	Pubchem ID :	13421547
Synonyms :

Calculated chemistry of [ 89402-42-6 ]

Physicochemical Properties

Num. heavy atoms :	12
Num. arom. heavy atoms :	6
Fraction Csp3 :	0.17
Num. rotatable bonds :	1
Num. H-bond acceptors :	6.0
Num. H-bond donors :	0.0
Molar Refractivity :	29.16
TPSA :	12.89 Å²

Pharmacokinetics

GI absorption :	High
BBB permeant :	Yes
P-gp substrate :	No
CYP1A2 inhibitor :	Yes
CYP2C19 inhibitor :	No
CYP2C9 inhibitor :	No
CYP2D6 inhibitor :	No
CYP3A4 inhibitor :	No
Log Kp (skin permeation) :	-5.81 cm/s

Lipophilicity

Log Po/w (iLOGP) :	1.67
Log Po/w (XLOGP3) :	2.27
Log Po/w (WLOGP) :	4.37
Log Po/w (MLOGP) :	2.44
Log Po/w (SILICOS-IT) :	3.25
Consensus Log Po/w :	2.8

Druglikeness

Lipinski :	0.0
Ghose :	None
Veber :	0.0
Egan :	0.0
Muegge :	2.0
Bioavailability Score :	0.55

Water Solubility

Log S (ESOL) :	-2.71
Solubility :	0.358 mg/ml ; 0.00195 mol/l
Class :	Soluble
Log S (Ali) :	-2.18
Solubility :	1.22 mg/ml ; 0.00665 mol/l
Class :	Soluble
Log S (SILICOS-IT) :	-3.47
Solubility :	0.062 mg/ml ; 0.000339 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	1.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	2.13

Safety of [ 89402-42-6 ]

Signal Word:	Danger	Class:	3
Precautionary Statements:	P210-P261-P305+P351+P338	UN#:	1993
Hazard Statements:	H225-H302-H315-H319-H335	Packing Group:	Ⅲ
GHS Pictogram:

Application In Synthesis of [ 89402-42-6 ]

* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.

Upstream synthesis route of [ 89402-42-6 ]
Downstream synthetic route of [ 89402-42-6 ]

[ 89402-42-6 ] Synthesis Path-Upstream 1~6

1
[ 69045-84-7 ]
[ 89402-42-6 ]

Yield	Reaction Conditions	Operation in experiment
47.6%	With potassium carbonate; cesium fluoride In dimethyl sulfoxide at 80 - 110℃; for 48 h; Inert atmosphere	1500 ml of DMSO, 363 g of cesium fluoride and 8 g of potassium carbonate were added to a 5000 ml reaction flask, heated in an oil bath, and depressurizedDMSO 600ml was concentrated and cooled to below 80°C. Under nitrogen protection, 318g (1.58 mol) of 2,3-dichloro-5-trifluoromethylpyridine was added and reacted at about 110°C for 48 hours. The yellow liquid was added with 600 ml of water, and the liquid was separated. The organic phase was dried over anhydrous magnesium sulfate. The crude product was filtered to obtain 188 g. Distillation yielded 139 g of a 100-102° C. fraction, which was 2,3-difluoro-5-trifluoromethylpyridine. The yield was 47.6percent.
40%	With potassium carbonate; cesium fluoride In 1-methyl-pyrrolidin-2-one at 110 - 120℃; for 15 - 24 h;	EXAMPLE 3; 2,3-difluoro-5-trifluoromethylpyridine (12-2); Equipment:; 2.5 l four-necked round bottom flask equipped with a thermometer, a mechanical stirrer a dropping funnel and an inert gas supply150 ml N-methyl-2-pyrrolidinone was evaporated at 110° C. and 25-30 mbar from a suspension of 2 l N-methyl-2-pyrrolidinone, 28 g potassium carbonate (202.6 mmol), and 615.0 g cesium fluoride (4.0 mol). The reaction mixture was treated with 170.0 g 2,3-dichloro-5-trifluoromethylpyridine (12-1, 779.2 mmol) and stirred at 120° C. for 24 h.The product 12-2 was directly distilled out of the reaction suspension at 95 to 110° C. and 40-50 mbar yielding 190 g of 12-2 as a mixture. 190 g of this mixture were extracted with 200 ml pentane and 400 ml water. After separation of the phases, the water phase was extracted with 2 l pentane. The combined pentane phase was distilled on a Sulzer-column at 40 to 100° C. yielding 60.0 g (40.4percent) of 12-2.GC analysis: 99.9 area-percent of 12-2; 4. Optimized Procedure to Difluoro Trifluoromethyl Pyridine (12-2); The synthesis of the 12-2 was elaborated starting from the corresponding dichloro compound 12-1 or from the very expensive chloro-fluoro compound 12-3. The reactivity of the chloro atom in the 2-position of 12-1 is significant higher compared with the chloro atom in the 3-position. Based on the known safety issue of DMSO in combination with bases like K₂CO₃at high temperatures like 120° C., DMSO was substituted by N-methylpyrrolidinone (NMP). The heterogenic reaction is very water-sensitive. Traces of water led to longer reaction time and/or incomplete conversion. Longer reaction time (more than 17 h at 120° C.) or higher temperature led, due to the instability of the product 12-2, to several unknown by-products, ending up as a black tar in the reaction vessel. Therefore, it was necessary to work with water free solvent. A substantial amount of CsF was needed for this reaction. CsF is very hygroscopic and contaminated the reaction mixture with water. Therefore, to completely eliminate water from the reaction mixture, a defined amount of NMP was evaporated prior to the addition of dichloro compound 12-1 to the suspension of K₂CO₃and CsF in NMP.

Reference： [1] Patent: CN104628679, 2018, B, . Location in patent: Paragraph 0061; 0064; 0065
[2] Patent: US2008/221327, 2008, A1, . Location in patent: Page/Page column 6; 9

2
[ 584-08-7 ]
[ 72537-17-8 ]
[ 89402-42-6 ]

Reference： [1] Patent: US4625035, 1986, A,
[2] Patent: US4480102, 1984, A,

3
[ 72600-67-0 ]
[ 89402-42-6 ]

Reference： [1] Patent: US4831148, 1989, A,

4
[ 124-38-9 ]
[ 584-08-7 ]
[ 72537-17-8 ]
[ 89402-42-6 ]

Reference： [1] Patent: US4480102, 1984, A,

5
[ 72537-17-8 ]
[ 89402-42-6 ]

Reference： [1] Patent: US2008/221327, 2008, A1, . Location in patent: Page/Page column 6

6
[ 89402-42-6 ]
[ 845614-11-1 ]

Yield	Reaction Conditions	Operation in experiment
28 g	With potassium carbonate In acetonitrile for 4 h; Reflux	The above oil, 11 g of 2,3-difluoro-5-trifluoromethylpyridine, 16 g of potassium carbonate and 350 ml of acetonitrile were added to a 1000 ml reaction flask, stirred, and heated under reflux for 4 hours. Cool and filter. The filtrate was concentrated to dryness to give a yellow oil which was recrystallized from ethanol to give 28 g of a white solid, which was the target product, Bitopertin. The total yield was 80.4percent.

Reference： [1] Patent: CN104628679, 2018, B, . Location in patent: Paragraph 0101; 0105

[ 89402-42-6 ] Synthesis Path-Downstream 1~82

1
[ 89402-42-6 ]
[ 22483-09-6 ]
[ 136352-99-3 ]

Reference： [1]Journal of Heterocyclic Chemistry,1991,vol. 28,p. 971 - 976

2
[ 89402-42-6 ]
[ 136353-00-9 ]

Reference： [1]Journal of Heterocyclic Chemistry,1991,vol. 28,p. 971 - 976

3
[ 89402-42-6 ]
[ 136382-41-7 ]

Reference： [1]Journal of Heterocyclic Chemistry,1991,vol. 28,p. 971 - 976

4
[ 89402-42-6 ]
[ 136352-97-1 ]

Reference： [1]Journal of Heterocyclic Chemistry,1991,vol. 28,p. 971 - 976

5
[ 89402-42-6 ]
[ 136353-01-0 ]

Reference： [1]Journal of Heterocyclic Chemistry,1991,vol. 28,p. 971 - 976

6
[ 89402-42-6 ]
[ 136353-02-1 ]

Reference： [1]Journal of Heterocyclic Chemistry,1991,vol. 28,p. 971 - 976

7
[ 89402-42-6 ]
[ 57260-71-6 ]
[ 897376-76-0 ]

Yield	Reaction Conditions	Operation in experiment
94%	With potassium carbonate; In acetonitrile; for 2h;Heating / reflux;	To a mixture of 120 mmol N-Boc-piperazine and 229 mmol potassium carbonate in 300 ml acetonitrile was slowly added a solution of 115 mmol <strong>[89402-42-6]2,3-difluoro-5-trifluoromethyl-pyridine</strong> (EP0104715) in 15 ml acetonitrile. The reaction mixture was refluxed for 2 hours. After such time, the mixture was filtered and the filtrate was concentrated in vacuo. The resulting white solid was dissolved in ethyl acetate, washed with water, dried over sodium sulfate and concentrated to yield the title compound as white solid (94% yield). MS (m/e): 294.2 (M-C4H8, 100%)

Reference： [1]Patent: US2006/149062,2006,A1 .Location in patent: Page/Page column 7
[2]Journal of Medicinal Chemistry,2010,vol. 53,p. 4603 - 4614

8
[ 12775-96-1 ]
[ 89402-42-6 ]
[ 108-98-5 ]
[ 216751-88-1 ]

Yield	Reaction Conditions	Operation in experiment
	With sodium hydroxide; In dichloromethane;	EXAMPLE 1 3-Fluoro-2-phenylthio-5-trifluoromethylpyridine Over a period of 2.5 h, 59.6 g (0.326 mol) of <strong>[89402-42-6]2,3-difluoro-5-trifluoromethylpyridine</strong> were added at 148-156 C. to 37.7 g (0.338 mol) of 98.7% pure thiophenol and 2.1 mg (0.01 mol %) of copper powder, and the mixture was stirred at 156-164 C. for 2 hours. After cooling, the residue was taken up in methylene chloride, washed with 0.5 N of aqueous sodium hydroxide solution and with water, dried over magnesium sulfate and concentrated under reduced pressure. 88.9 g (100% of theory) of the title compound of n24/D=1.5539 were obtained.
	In dichloromethane;	Example 4 3-Fluoro-2-phenylthio-5-trifluoromethylpyridine At 148-156 C., 59.6 g (0.326 mol) of <strong>[89402-42-6]2,3-difluoro-5-trifluoromethylpyridine</strong> were added over a period of 2.5 h to 37.7 g (0.338 mol) of 98.7% pure thiophenol and 2.1 mg (0.01 mol %) of copper powder, and the mixture was stirred at 156-164 C. for 2 hours. After cooling, the residue was taken up in methylene chloride, washed with 0.5 N aqueous sodium hydroxide solution and water, dried over magnesium sulfate and concentrated under reduced pressure. 88.9 g (100% of theory) of the title compound of

Reference： [1]Patent: US6420314,2002,B1
[2]Patent: US6191280,2001,B1

9
[ 149728-97-2 ]
[ 89402-42-6 ]
α-anti-methoxyimino-N-methyl-2-(3-fluoro-5-trifluoromethyl-2-pyridyloxy)methylphenyl-acetamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	In N-methyl-acetamide; sodium chloride; N,N-dimethyl-formamide;	Example 1 Preparation of alpha-anti-methoxyimino-N-methyl-2-(3-fluoro-5-trifluoromethyl-2-pyridyloxy)methylphenyl-acetamide (No. I-1) A suspension of 1.4 g of sodium hydride in 15 ml of dimethylformamide (DMF) was mixed with a solution of 11.1 g of (E) -2-[2-(hydroxymethyl) phenyl]-2-methoxyimino-N-methylacetamide in 120 ml of DMF. The reaction mixture was exposed to ultrasound for about 10 min and subsequently stirred at about 20 to 25 C. for 1 h. A solution of 9.2 g of <strong>[89402-42-6]2,3-difluoro-5-trifluoromethyl-pyridine</strong> in 85 ml of DMF was added dropwise and the mixture was stirred at 22 to 25 C. for about 24 h. The reaction mixture was taken up in 1 l of dilute sodium chloride solution and extracted with methyl tert-butyl ether (MtBE). The combined organic phases were washed with water and dried. The solvent was distilled off under reduced pressure and the residue was subjected to silica gel chromatography (cyclohexane/MtBE=2:1), affording 6.9 g of the title compound as a pale powder of mp. 112-116 C. IR (cm-1): 3380, 1659, 1623, 1498, 1453, 1336, 1272, 1151, 1131, 1040.

Reference： [1]Patent: US6372766,2002,B1

10
[ 89402-42-6 ]
[ 590-17-0 ]
N-Cyanomethyl-3-fluoro-5-(trifluoromethyl-2-pyridinone [ No CAS ]
N-cyanomethyl-3,5-bis(trifluoromethyl)-2-pyridinone [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With sodium hydroxide; In 1-methyl-pyrrolidin-2-one;	EXAMPLE 2 Preparation of N-Cyanomethyl-3-fluoro-5-(trifluoromethyl-2-pyridinone To a solution of 183 g (1.00 mole) of 2,3-di-fluoro-5-(trifluoromethyl)pyridine in 1200 ml of N-methyl-2-pyrrolidinone was added rapidly with stirring 750 ml of 10 percent aqueous sodium hydroxide. An exothermic reaction ensued. The reaction mixture was cooled in an ice bath to bring the temperature down to about 45 C., and was stirred for 0.5 hr. It was then treated with 146 g (1.22 mole) of monobromoacetonitrile dissolved in 200 ml of N-methyl-2-pyrrolidinone, and the resulting reaction mixture was stirred for another 45 minutes. The addition of 1.2 1 of water resulted in the separation of a white solid, which was isolated by filtration, washed with water and dried. Another crop of a white solid separated out when the mother liquor was allowed to stand overnight. This solid was also separated by filtration and dried. The solids were combined and characterized as the desired product by infrared, nmr, and elemental (C,H,N) analysis and found to have a melting point of 141-143 C. The overall yield was 200 g (90.7 percent of theory). The compounds N-cyanomethyl-4-(trifluoro-methyl)-2-pyridinone, m.p. 134-136 C., and N-cyanomethyl-3,5-bis(trifluoromethyl)-2-pyridinone, m.p. 88-99 C., were prepared similarly and found to have compatible elemental (C,H,N) analyses and nmr and infrared spectra.

Reference： [1]Patent: US4931452,1990,A

11
[ 123-08-0 ]
[ 89402-42-6 ]
[ 134872-12-1 ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate; In water; acetonitrile;	EXAMPLE XV 4-(5-(Trifluoromethyl)-3-fluoro-2-pyridyloxy)benzaldehyde STR53 To a solution of 36.6 g (0.20 mol) of <strong>[89402-42-6]2,3-difluoro-5-(trifluoromethyl)pyridine</strong> in 150 ml of acetonitrile was added 25.6 g (0.21 mol) of p-hydroxybenzaldehyde, 29.0 g (0.21 mol) of powdered potassium carbonate and 50 mL of acetonitrile. The slurry was stirred at ambient temperature for 21 hours and then diluted with 300 mL of water. The organic layer was separated in a separatory funnel and washed twice with 150 mL portions of water followed by washing with 100 mL of a 10 percent potassium carbonate solution. The mixture was then dried over sodium sulfate and the solvent removed in vacuo leaving 48.0 g (84 percent of theoretical) of the above named compound, a light yellow oil, as the product; 1 H NMR (CDCl3): 7.3-8.3 (m, 6H, Ar), 10.0 (s, 1H, CH(O).

Reference： [1]Patent: US4983211,1991,A

12
[ 134872-20-1 ]
[ 89402-42-6 ]
2-Propionyl-3-hydroxy-5-(4-(5-(trifluoromethyl)-3-fluoro-pyridin-2-ylthio)phenyl)cyclohex-2-en-1-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate; In ethanol; dichloromethane; water; acetonitrile;	EXAMPLE X 2-Propionyl-3-hydroxy-5-(4-(5-(trifluoromethyl)-3-fluoro-2-pyridylthio)phenyl)cyclohex-2-en-1-one STR48 To a solution of 4.0 g (0.0145 mol) of 3-hydroxy-5-(4-mercaptophenyl)-2-propionyl-cyclohex-2-en-1-one in 50 mL of acetonitrile was added 3.90 g (0.0212 mol) of <strong>[89402-42-6]2,3-difluoro-5-(trifluoromethyl)pyridine</strong> and 4.50 g (0.0326 mol) of powdered potassium carbonate. The mixture was stirred one hour at ambient temperature and then heated at reflux for 1.5 hours and cooled to room temperature. The reaction mixture was diluted with 150 mL of water and 150 mL of methylene chloride. The organic layer was separated, washed twice with 150 mL portions of water and dried over Na2 SO4. The solvent was removed in vacuo leaving 5.7 g of the crude product which was purified by column chromatography using methylene chloride as the eluent. Recrystallization of the crude from ethanol gave the above named product in a yield of 2.25 g (35 percent of theoretical). The product melted at 152-154 C.; 1 H NMR (CDCl3): delta 1.10 (t, 3H, CH3 CH2 --), 2.55-3.65 (m, 7H, ring protons and CH3 CH2 --), 7.15-8.50 (m, 6H, ArH), 18.2 (s, 1H, OH).

Reference： [1]Patent: US4983211,1991,A

13
[ 89402-42-6 ]
[ 124432-61-7 ]

Yield	Reaction Conditions	Operation in experiment
	In tetrahydrofuran; methanol;	EXAMPLE 3 Preparation of 2,3-Dimethoxy-5-(trifluoromethyl)pyridine Sodium hydride in an oil dispersion (8.0 g of 60 percent, 0.20 mol) was extracted with hexane to remove oil and suspended in 30 ml of tetrahydrofuran and to this 5.5 ml (0.14 mol) of anhydrous methanol was added dropwise with stirring. After about 10 min, 9.16 g (0.05 mol) of <strong>[89402-42-6]2,3-difluoro-5-(trifluoromethyl)-pyridine</strong> was added. An exothermic reaction ensued which increased the temperature to about 60 C. The mixture was then heated at reflux for 6 hours and then a small amount of methanol was added. The mixture was allowed to cool and was thereafter poured onto ice. The resulting mixture was extracted several times with ether. The combined ether extracts were dried over sodium sulfate and concentrated by evaporation under reduced pressure to obtain 9.0 g (87 percent of theory) of the title compound as a white crystalline solid melting at 22-23.5 C. The proton nmr spectrum was consistent with the assigned structure.

Reference： [1]Patent: US4931452,1990,A

14
[ 60075-04-9 ]
[ 584-08-7 ]
[ 89402-42-6 ]
(+)-2-[4-(3-fluoro-5-trifluoromethylpyridin-2-yloxy)-phenoxy]-propionic acid methyl ester [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
96%	In water;	Example 3 Preparation of Methyl R-2-(4-((3-Fluoro-5-trifluoromethyl-2-pyridinyl)-oxy)phenoxy)propionate STR6 In a 1L flask equipped with a mechanical stirrer, condenser and addition funnel was charged 183 g (1.0 mole) of <strong>[89402-42-6]2,3-difluoro-5-trifluoromethylpyridine</strong> and 193 g (1.4 moles) of anhydrous K2 CO3 with a particle size range between 100 and 350 microns. Under constant agitation, the slurry was heated to 65 C. and 198 g (1.0 moles) of molten methyl R-2-(4-hydroxyphenoxy)propionate (R/S=93/7) was gradually added. The reaction mixture was heated for 16 hr at 85 C. and was subsequently washed 5 times using hot water. The washed product was stripped of residual water using a rotary evaporator at 75 C. and 30 mm Hg. Product having a purity of 99.2 percent and an R/S ratio of 93/7 (no racemization) was recovered in a 96 percent yield.

Reference： [1]Patent: US5049675,1991,A

15
[ 89402-42-6 ]
[ 108-46-3 ]
[ 6025-45-2 ]

Yield	Reaction Conditions	Operation in experiment
	With NaH; In dimethyl sulfoxide; paraffin;	EXAMPLE 1 Preparation of 3-((3-fluoro-5-(trifluoromethyl)-2-pyridinyl)oxy)phenol The disodium salt of resorcinol was prepared from 5.24 g resorcinol and 4 g of 50 percent NaH dispersed in paraffin which was washed with hexane to remove any paraffin. The salt was suspended in 150 ml of DMSO by stirring at ambient temperature for one-half hour after which 4 g of <strong>[89402-42-6]2,3-difluoro-5-trifluoromethylpyridine</strong> were added. Stirring was continued at ambient temperature for three hours. The reaction mixture was diluted with water, acidified with dilute HCl and extracted with ether. The ether extract was washed with water, dried over anhydrous MgSO4 and concentrated to a brown oil which was shown by NMR and GC to consist mainly of the desired product, the main impurity being the starting material.

Reference： [1]Patent: US4599105,1986,A

Yield	Reaction Conditions	Operation in experiment
		EXAMPLE 3 Preparation of 2,3-difluoro-5-(trifluoromethyl)pyridine A 500 ml 4-neck round bottom flask, equipped with an air driven mechanical stirrer and fitted with a thermometer, a distillation condenser and a stopper, was charged with 500 ml of DMSO, 1 g anhydrous K2 CO3 and 25 g (0.165 mole) of CsF (one third of total CsF). The flask was heated with a heating mantle and about 100 ml of DMSO was distilled at ~110 C./~40 mm Hg to dry the reaction mixture. The reaction mixture was cooled to about 75 C. and N2 was reintroduced into the flask. The distillation condenser was replaced by a reflux condenser which was vented to a dry ice trap with a N2 atmosphere. To the reaction mixture was added 65.7 g of 3-chloro-2-fluoro-5-(trifluoromethyl)pyridine (0.329 mole) in one portion, with constant agitation, and the temperature of the reaction mixture was increased to between 120-125 C. with the aid of a Thermowatch temperature controller. In 2.5 hours and 21.5 hours after the addition of the 3-chloro-2-fluoro-5-(trifluoromethyl)pyridine, additional 25 g portions of CsF were added to the reaction mixture for a total of 75 g of CsF in the reaction mixture. The reaction was allowed to run 69 hours at which time the reaction mixture appeared black with dark solids on the walls of the flask. A distillation condenser was attached to the flask and the reflux condenser was removed to allow the removal of the crude product by distillation (pressure=210 mm Hg; temperature (overhead)=90-130 C.; temperature (pot)=~160 C.). To prevent the volatile product from being lost, the receiver was cooled in a dry ice/acetone bath. The distillation was continued until the head temperature stopped increasing at which time the vacuum was released, the receivers changed and the distillation resumed. An additional 10 ml was distilled over at a temperature of 130 C. and the distillation was stopped. The crude material was extracted with 100 ml of water and dried over 0.5 g of 4 A molecular sieves to give 35.1 g of 2,3-difluoro-5-(trifluoromethyl)pyridine. Elemental analysis results of the product were: Found: C, 39.06; H, 1.15; N, 7.88; Cl, 0.15. Theoretical: C, 39.36; H, 1.09; N, 7.65; Cl, 0.

17
[ 584-08-7 ]
[ 72537-17-8 ]
[ 89402-42-6 ]

Yield	Reaction Conditions	Operation in experiment
	With cesium fluoride; In dimethyl sulfoxide;	EXAMPLE 2 Preparation of 2,3-difluoro-5-(trifluoromethyl)pyridine A 100 ml 4-neck round bottom flask, containing a magnetic stir bar and fitted with a thermometer, nitrogen inlet and distillation condenser, was charged with 75 ml of DMSO, 0.5 g of anhydrous K2 CO3 and 22.8 g (0.15 mole) of CsF. The reaction mixture was heated to 115 C. at 57 mm Hg so that about 20 ml of DMSO was distilled to dry the reaction mixture. The light yellow reaction mixture was cooled to 65 C. and 20 g (0.1 mole) of <strong>[72537-17-8]3-chloro-2-fluoro-5-(trifluoromethyl)pyridine</strong> was added through a pressure equalizing addition funnel which replaced the distillation condenser. After a dry ice condenser was attached to the flask the reaction temperature was maintained at 105-115 C. for 46.5 hours with constant agitation. The reaction mixture was black with dark solids on the sides of the flask. A short path distillation condenser was attached to the flask and 13 g of crude product was collected in a receiver, which was cooled in a dry ice/acetone bath (pressure=210 mm Hg; temperature (overhead)=85-130 C.; temperature (pot)=125-160 C.). This crude product was extracted with water to remove any residual DMSO and dried over 4 A molecular sieves (11.5 g crude product; 11 g crude product after drying). The product was then transferred to a 25 ml round bottom flask and distilled at 102 C. (uncorrected)/760 mm Hg through a Vigreaux column resulting in 9.3 g of substantially pure 2,3-di-fluoro-5-(trifluoromethyl)pyridine. The isolated yield of desired product was calculated to be 48.4% of theoretical. The structure of the product was confirmed by its nuclear magnetic resonance (NMR) spectra. Elemental analysis results for the product were: Theoretical: C, 39.36; H, 1.09; N, 7.65; Cl, 0. Found: C, 38.44; H, 1.01; N, 7.79; Cl, 0.25.
	With cesium fluoride; In dimethyl sulfoxide;	EXAMPLE 2 Preparation of 2,3-difluoro- 5-(trifluoromethyl)pyridine STR3 A 100 ml 4-neck round bottom flask, containing a magnetic stir bar and fitted with a thermometer, nitrogen inlet and distillation condenser, was charged with 75 ml of DMSO, 0.5 g of anhydrous K2 CO3 and 22.8 g (0.15 mole) of CsF. The reaction mixture was heated to 115 C. at 57 mm Hg so that about 20 ml of DMSO was distilled to dry the reaction mixture. The light yellow reaction mixture was cooled to 65 C. and 20 g (0.1 mole) of <strong>[72537-17-8]3-chloro-2-fluoro-5-(trifluoromethyl)pyridine</strong> was added through a pressure equalizing addition funnel which replaced the distillation condenser. After a dry ice condenser was attached to the flask the reaction temperature was maintained at 105-115 C. for 46.5 hours with constant agitation. The reaction mixture was black with dark solids on the sides of the flask. A short path distillation condenser was attached to the flask and 13 g of crude product was collected in a receiver, which was cooled in a dry ice/acetone bath (pressure=210 mm Hg; temperature (overhead)=85-130 C.; temperature (pot)=125-160 C). This crude product was extracted with water to remove any residual DMSO and dried over 4A molecular sieves (11.5 g crude product; 11 g crude product after drying). The product was then transferred to a 25 ml round bottom flask and distilled at 102 C. (uncorrected)/760 mm Hg through a Vigreaux column resulting in 9.3 g of substantially pure 2,3-difluoro-5-(trifluoromethyl)pyridine. The isolated yield of desired product was calculated to be 48.4% of theoretical. The structure of the product was confirmed by its nuclear magnetic resonance (NMR) spectra. Elemental analysis results for the product were: Theoretical: C, 39.36; H, 1.09; N, 7.65; Cl, 0. Found: C, 38.44; H, 1.01; N, 7.79; Cl, 0.25.

Reference： [1]Patent: US4625035,1986,A
[2]Patent: US4480102,1984,A

18
[ 124-38-9 ]
[ 584-08-7 ]
[ 72537-17-8 ]
[ 89402-42-6 ]

Yield	Reaction Conditions	Operation in experiment
	With cesium fluoride; In dimethyl sulfoxide;	EXAMPLE 3 Preparation of 2,3-difluoro-5-(trifluoromethyl)pyridine STR4 A 500 ml 4-neck round bottom flask, equipped with an air-driven mechanical stirrer and fitted with a thermometer, a distillation condenser and a stopper, was charged with 500 ml of DMSO, 1 g anhydrous K2 CO3 and 25 g (0.165 mole) of CsF (one third of total CsF). The flask was heated with a heating mantle and about 100 ml of DMSO was distilled at ~110 C./~40 mm Hg to dry the reaction mixture. The reaction mixture was cooled to about 75 C. and N2 was reintroduced into the flask. The distillation condenser was replaced by a reflux condenser which was vented to a dry ice trap with a N2 atmosphere. To the reaction mixture was added 65.7 g of <strong>[72537-17-8]3-chloro-2-fluoro-5-(trifluoromethyl)pyridine</strong> (0.329 mole) in one portion, with constant agitation, and the temperature of the reaction mixture was increased to between 120-125 C. with the aid of a thermowatch temperature controller. In 2.5 hours and 21.5 hours after the addition of the <strong>[72537-17-8]3-chloro-2-fluoro-5-(trifluoromethyl)pyridine</strong>, additional 25 g portions of CsF were added to the reaction mixture for a total of 75 g of CsF in the reaction mixture. The reaction was allowed to run 69 hours at which time the reaction mixture appeared black with dark solids on the walls of the flask. A distillation condenser was attached to the flask and the reflux condenser was removed to allow the removal of the crude product by distillation (pressure=210 mm Hg; temperature (overhead)=90-130 C.; temperature (pot)=~160 C.). To prevent the volatile product from being lost, the receiver was cooled in a dry ice/acetone bath. The distillation was continued until the head temperature stopped increasing at which time the vacuum was released, the receivers changed and the distillation resumed. An additional 10 ml was distilled over at a temperature of 130 C. and the distillation was stopped. The crude material was extracted with 100 ml of water and dried over 0.5 g of 4A molecular sieves to give 35.1 g of 2,3-difluoro-5-(trifluoromethyl)pyridine. Elemental analysis results of the product were: Found: C, 39.06; H, 1.15; N, 7.88; Cl, 0.15.

Reference： [1]Patent: US4480102,1984,A

19
[ 89402-42-6 ]
4-((3-Fluoro-5-(Trifluoromethyl)-2-Pyridinyl)Oxy)Phenol [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
14.5 g (71%)	With potassium hydroxide; hydroquinone; In hexane; dimethyl sulfoxide; ethyl acetate;	(a) 4-(3-fluoro-5-trifluoromethylpyridin-2-yloxy)-phenol A mixture of 16.5 g (0.15 mol) of hydroquinone, 19.1 g (0.3 mol) of potassium hydroxide (88%) in 600 ml of dimethylsulfoxide is stirred at room temperature under a nitrogen atmosphere until everything is dissolved. A solution of 13.7 g (0.075 mol) of <strong>[89402-42-6]2,3-difluoro-5-trifluoromethyl-pyridine</strong> in 25 ml of dimethylsulfoxide is added dropwise at a temperature of 15-20. The reaction mixture is then stirred at room temperature for 24 hours. Then it is poured into ice/water and the mixture is acidified with hydrochloric acid, extracted with methylene chloride, washed with water, dried over magnesium sulfate, filtered and evaporated to dryness. The residue crystallizes in hexane/ethyl acetate to yield 14.5 g (71%) of white crystals, melting at 97.

Reference： [1]Patent: US4832736,1989,A

20
[ 72600-67-0 ]
[ 89402-42-6 ]

Yield	Reaction Conditions	Operation in experiment
	With caesium fluoride; potassium fluoride; In sulfolane;	(c) 47.7 g (0.82 mol) of potassium fluoride and 10.0 g (0.065 mol) of caesium fluoride are suspended in 300 ml of sulfolane and the suspension is heated to 140 C. 60 ml of sulfolane are distilled off by decreasing the pressure and subsequently 65.6 g (0.329 mol) of <strong>[72600-67-0]2-chloro-3-fluoro-5-trifluoromethylpyridine</strong> and 1.3 g (0.004 mol) of 18-crown-6 are added. The reaction mixture is stirred for 48 hours at 140 C. and subsequently distilled by introducing steam. The oil is separated and the aqueous phase is extracted twice with a small amount of ether. The organic phases are purified, dried with a small amount of magnesium sulfate and filtered. Distillation affords 54.8 g (91% of theory) of 2,3-difluoro-5-trifluoromethylpyridine, b.p. 100-102 C. (980 mbar).

Reference： [1]Patent: US4831148,1989,A

21
[ 89402-42-6 ]
[ 375853-82-0 ]
[ 943238-19-5 ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate;tetrakis(triphenylphosphine) palladium(0); dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; In N,N-dimethyl-formamide; at 125℃; for 0.5h;Microwave;	To 2-bromo-5-(trifluoromethyl) pyridine (200mg), were added 1-1- bis(dirhohenylpliosphonyl)ferrocenedichloropalladium (TT) chloride 1 :1 complex with dichloromcthanc (lOOmg), Tctrakis-(triphcnylphosphino)-palladium (0) (lOOmg), potassium carbonate (200mg), [N-tert-butoxy carbonyl]-l,2,3,6-tetrahydropyridine-4-boronic acid pinacol ester (410mg) and dimethylformamide (3.5ml). Resultant suspension was heated in the microwave at 125C for 30min. It was then preabsorbed onto silica and purification was done using a 1Og bond elute cartridge eluting with 3:1 cyclohexane: dichloromethane then dichloromethane to give an orange oil. To the orange oil was added trifluroacctic acid : dichloromcthanc (95:5) (1.5ml). The resultant solution was allowed to stand at room temperature for 30min before evaporating in vacuo and purifying on MDAP to give 5-(Mfluoromethyl)-1^2^3^6'-tetrahydro-2,4'-bipyridine as a white solid (70mg). MS(ESI) 229 [M+H]+.To (l S)-(+) -10- camphorsulphonyl chloride (40mg) were added 5-(trifluoromethyl)- r,2',3',6'-tctrahydro-2,4'-bipyridinc (55mg), diisopropylcthylaminc (10OuI) and Dimethylformamide (ImI). The resultant solution was stirred at room temperature overnight.(l 6hr). The reaction <n="64"/>mixture was evaporated in vacuo and purified on Mass Directed Auto prep (MDAP) to give 30mg of (lS,4i?)-7,7-dimethyl-l-([5-(trifluoromethyl)-31,6'-dihydro-2,41-bipyridm-r(21i)- yl]sulfonyl}methyl)bicyclo[2.2.1]heptan-2-one as a white solid. MS(ESI) 443 [M+H]+.

Reference： [1]Patent: WO2007/76318,2007,A2 .Location in patent: Page/Page column 62

22
[ 278788-66-2 ]
[ 89402-42-6 ]
[ 943238-14-0 ]

Yield	Reaction Conditions	Operation in experiment
	With N-ethyl-N,N-diisopropylamine; In dimethyl sulfoxide; at 80℃;	Into a 5-mL-pressure tube was added 183mg (l.Ommol) of 2,3-difluoro-5- (trifluoromethyl)pyridine, 216mg (l.Ommol) of 1,1-dimethylethyl (3i?)-3-(hydroxymethy I)-I- piperazinecarboxylate, 0.2mL DlEA and 1.OmL DMSO. The mixture was heated at 80 C for overnight. The resulting mixture were filtered and concentrated in vacuo. The residue was purified by using a Gilson preparative HPLC system with a Waters Xterra (C-18) column 100 mm by 50 mm ID, eluting with 20% B to 99% B in 10 min, where A = H2O and B = CH3CN pumped at 150 mL/min to yield 1,1-dimethylethyl (3i?)-4-[3-fluoro-5-(trifluoromethyl)-2-pyridinyl]-3- (hydroxymethyl)- 1 -piperazinecarboxylate as a solid. MS(ESI) 380 [M+H] +.To 20mg (0.053mmol) of 1,1-dimethylethyl (3i?)-4-[3-fluoro-5-(trifluoromethyl)-2- pyridinyl]-3-(hydroxymethyl)-l -piperazinecarboxylate was added 0.5mL DMSO and 20mg of tBuOK in a 5-mL-pressure tube. The mixture was heated at 110 C for overnight. The mixture was filtered and the solution was purified by using a Gilson preparative HPLC system with a Waters Xterra (C- 18) column 100 mm by 50 mm ID, eluting with 20% B to 99% B in 10 min, where A = H2O and B = CH3CN pumped at 150 mL/min to yield 1,1-dimethylethyl (6ai?)-3-(trifluoromethyl)- 6a,7,9,10-tetrahydropyrazino[l,2-rf]pyrido[3,2-][l,4]oxazine-8(6H)-carboxylate as a solid. MS(ESI) 360 [M+H]+.To 40mg of (0.1 lmmol) of 1,1-dimethylethyl (6alphai?)-3-(trifluoromethyl)-6alpha,7,9,10- tetrahydropyrazino[l,2-cr\|pyrido[3,2-][l,4]oxazme-8(6H)-carboxylate was added ImL DCM and 0.5mL 50% of TFA in DCE. The mixture was stirred at rt for 6h and concentrated in vacuo (the extra TFA was removed by adding DCE and re-concentrating) to yield crude the TFA salt of (6ocR)- 3-(trifluoromethyl)-6,6alpha,7,8,9,10-hexahydropyrazino[l,2-rf]pyrido[3,2-A][l,4]oxazine. MS(ESI) 260 [M+H]1. <n="63"/>The above TFA salt of (6alphai?)-3-(trifluoromethyl)-6,6alpha,7,8,9,10-hexahydropyrazino[l,2- rf]pyrido[3,2-ib][l,4]oxazine were dissolved in 1.OmL DCM and 0.3mL DIEA. Then lOOmg (mmol) of (S)-(+)-Camphotau sulfonylchloride in 0.5mL DCM was slowly added at 0 C. The mixture was stirred at rt for 2h. The resulting solution was concentrated in vacuo. The residue was purified by using a Gilson preparative HPLC system with a Waters Xterra (C- 18) column 100 mm by 50 mm ID, eluting with 20% B to 99% B in 10 min, where A = H2O and B = CH3CN pumped at 150 mL/minto yield (l£,4Z?)-7,7-dimethyl-l-([(6 alphai?)-3-(trifluoromethyl)-6 alpha,7,9,10- tetrahydropyrazino[ 1 ,2-<s?]pyrido[3,2-6] [ J ,4]oxazin-8(6H)-yl]sulfonyl} methyl)bicyclo[2.2.1 ]heptan- 2-one (34mg, 65% yield for 2 steps). MS (ESI): 474 [M+H]+

Reference： [1]Patent: WO2007/76318,2007,A2 .Location in patent: Page/Page column 61

23
[ 943238-09-3 ]
[ 89402-42-6 ]
(1S,4R)-1-([4-[3-fluoro-5-(frifluoromethyl)-2-pyridinyl]-3-(hydroxymethyl)-piperazinyl]sulfonyl}methyl)-7,7-dimethylbicyclo[2.2.1]heptan-2-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
44%	With N-ethyl-N,N-diisopropylamine; In dimethyl sulfoxide; at 50℃; for 48h;	Into a 25mL flask was added 400mg (3.45mmol) of 2-piperazinylmethanol and ImL DIEA and 4mL DMF. An aliquot of 560mg (2.24mmol) of [(lS,4i?)-7,7-dimethyl-2- oxobicyclo[2.2.1]hept-l-yl]methanesulfonyl chloride in ImL of DMF was added dropwise. The mixture was stirred at rt for 4h. After filtration, the reaction solution was concentrated and the residue was purified by using a Gilson preparative HPLC system with a Waters Xterra (C-18) column 100 mm by 50 mm ID, eluting with 5% B to 99% B in 10 min, where A = H2O and B = CH3CN pumped at 150 mL/min (fraction collection based on UV trace at 214nm with sensitivity set as low as 2) to yield (^^^-^([S-°iydroxymethy^-l-piperazinyysulfonyllmethyl)-?,?- dimcthylbicyclo[2.2.1]hcptan-2-onc (500mg, 67%). MS (ESI): 331 [M+H]+. To 190mg (0.576mmol) of above (l£,4£)-l-([3-(hydroxymethyl)-l- piperazinyl]sulfonyl}methyl)-7,7-dimethylbicyclo[2.2.1]heptan-2-one was added 0.2mL of DIEA and ImL DMSO. Then An aliquot of 105mg (0.576mmol) of 2,3-difluotauo~5- trifluoromethylpyridine was added. The mixture was heated at 500C for two days. After filtration, the reaction solution was concentrated (to remove DIEA) and the residue was purified by using a Gilson preparative HPLC system with a Waters Xterra (C- 18) column 100 mm by 50 mm ID, eluting with 20% B to 99% B in 10 min, where A = H2O and B = CH3CN pumped at 150 mL/min to yield ( 1S,4R)- 1 -( { [4- [3-fluoro-5-(trifluoromethyl)-2-pyridiny l]-3 -(hydroxymethyl)- 1 - piperaziiiyllsulfonyllmethyO^J-dimethylbicycloP^.llheptan^-one (125mg, 44%). MS (ESI): 494 [M+H]+.

Reference： [1]Patent: WO2007/76318,2007,A2 .Location in patent: Page/Page column 32

24
[ 943238-13-9 ]
[ 89402-42-6 ]
(1S,4R)-1-[({(2S)-4-[3-fluoro-5-(trifluoromethyl)-2-pyridinyl]-2-methyl-1-piperazinyl}sulfonyl)methyl]-7,7-dimethylbicyclo[2.2.1]heptan-2-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With N-ethyl-N,N-diisopropylamine; In dimethyl sulfoxide; at 100℃; for 0.0833333h;Microwave;	To a solution of [(l,l-dimethylethyl)oxy][(3iS)-3-methyl-l-piperazinyl]methanol (160mg, 0.8mmol) in DCM (2ml) was added DIEA (0.2ml) and [(15,4i?)-7,7-dimethyl-2- <n="39"/>oxobicyclo[2.2.1]hept-l-yl]methanesulfonyl chloride (200mg, 0.8mmol). The mixture was stirred at room temperature for 4h. Solvents were removed and the resulting crude product, 1,1-dimethylethyl (3£)-4-( { [(15,4i?)-7,7-dimethyl-2-oxobicyclo[2.2.1 ]hept- 1 -yljmethyl} sulfonyl)-3 -methyl- 1 - piperazinecarboxylate was used in the next reaction without further purification. To a mixture of the above crude product in MeOH (2ml) was added HCl in dioxane (4M,0.8ml). The mixture was stirred at room temperature for 18h. Solvents were removed under reduced pressure. The resulting residue was partitioned between DCM and saturated aqueous NaHCCb. The organic layer was washed with water, brine solution and dried over Na2SO4. After solvent was evaporated under reduced pressure, the resulting crude product, (15',4i?)-7,7-dimcthyl- 1 -( [{2S)-2- methyl-l-piperazinyl]sulfonyl}methyl)bicyclo[2.2.1]heptan-2-one, was used for the next reaction without further purification.To a mixture of the above crude product in DMSO (1.5ml) in 5mL microwave reactor was added 2,3-difluoro-5-(trifluoromethyl)pyriditauie (150mg, 0.8mtaunol) and DTEA (0.15ml). The mixture was heated in Biotagc microwave at 100 C for 5 min. The crude material was purified by using a Gilson preparative HPLC system with a Waters Xterra (C- 18) column 100 mm by 50 mm ID, eluting with 20% B to 99% B in 10 min, where A = H2O and B = CH3CN pumped at 150 mL/min to yield the desired product (l)S',4JR)-l-[({(2iS)-4-[3-fluoro-5-(trifluoromethyl)-2-pyridinyl]-2-methyl- l-piperazinyl}sulfonyl)methyl]-7,7-dimethylbicyclo[2.2.1]heptan-2-one as a white solid (249mg, 65% yield over 3 steps). MS (ESl): 478 [M+H]+.

Reference： [1]Patent: WO2007/76318,2007,A2 .Location in patent: Page/Page column 38

25
[ 72537-17-8 ]
[ 89402-42-6 ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate; cesium fluoride; In 1-methyl-pyrrolidin-2-one; at 120℃; for 16h;Product distribution / selectivity;	4. Optimized Procedure to Difluoro Trifluoromethyl Pyridine (12-2); The synthesis of the 12-2 was elaborated starting from the corresponding dichloro compound 12-1 or from the very expensive chloro-fluoro compound 12-3. The reactivity of the chloro atom in the 2-position of 12-1 is significant higher compared with the chloro atom in the 3-position. Based on the known safety issue of DMSO in combination with bases like K2CO3 at high temperatures like 120 C., DMSO was substituted by N-methylpyrrolidinone (NMP). The heterogenic reaction is very water-sensitive. Traces of water led to longer reaction time and/or incomplete conversion. Longer reaction time (more than 17 h at 120 C.) or higher temperature led, due to the instability of the product 12-2, to several unknown by-products, ending up as a black tar in the reaction vessel. Therefore, it was necessary to work with water free solvent. A substantial amount of CsF was needed for this reaction. CsF is very hygroscopic and contaminated the reaction mixture with water. Therefore, to completely eliminate water from the reaction mixture, a defined amount of NMP was evaporated prior to the addition of dichloro compound 12-1 to the suspension of K2CO3 and CsF in NMP.

Reference： [1]Patent: US2008/221327,2008,A1 .Location in patent: Page/Page column 6

26
[ 69045-84-7 ]
[ 89402-42-6 ]

Yield	Reaction Conditions	Operation in experiment
47.6%	With potassium carbonate; cesium fluoride; In dimethyl sulfoxide; at 80 - 110℃; for 48h;Inert atmosphere;	1500 ml of DMSO, 363 g of cesium fluoride and 8 g of potassium carbonate were added to a 5000 ml reaction flask, heated in an oil bath, and depressurizedDMSO 600ml was concentrated and cooled to below 80C. Under nitrogen protection, 318g (1.58 mol) of 2,3-dichloro-5-trifluoromethylpyridine was added and reacted at about 110C for 48 hours. The yellow liquid was added with 600 ml of water, and the liquid was separated. The organic phase was dried over anhydrous magnesium sulfate. The crude product was filtered to obtain 188 g. Distillation yielded 139 g of a 100-102 C. fraction, which was 2,3-difluoro-5-trifluoromethylpyridine. The yield was 47.6%.
40 - 40.4%	With potassium carbonate; cesium fluoride; In 1-methyl-pyrrolidin-2-one; at 110 - 120℃; under 18.7519 - 22.5023 Torr; for 15 - 24h;Product distribution / selectivity;	EXAMPLE 3; 2,3-difluoro-5-trifluoromethylpyridine (12-2); Equipment:; 2.5 l four-necked round bottom flask equipped with a thermometer, a mechanical stirrer a dropping funnel and an inert gas supply150 ml N-methyl-2-pyrrolidinone was evaporated at 110 C. and 25-30 mbar from a suspension of 2 l N-methyl-2-pyrrolidinone, 28 g potassium carbonate (202.6 mmol), and 615.0 g cesium fluoride (4.0 mol). The reaction mixture was treated with 170.0 g 2,3-dichloro-5-trifluoromethylpyridine (12-1, 779.2 mmol) and stirred at 120 C. for 24 h.The product 12-2 was directly distilled out of the reaction suspension at 95 to 110 C. and 40-50 mbar yielding 190 g of 12-2 as a mixture. 190 g of this mixture were extracted with 200 ml pentane and 400 ml water. After separation of the phases, the water phase was extracted with 2 l pentane. The combined pentane phase was distilled on a Sulzer-column at 40 to 100 C. yielding 60.0 g (40.4%) of 12-2.GC analysis: 99.9 area-% of 12-2; 4. Optimized Procedure to Difluoro Trifluoromethyl Pyridine (12-2); The synthesis of the 12-2 was elaborated starting from the corresponding dichloro compound 12-1 or from the very expensive chloro-fluoro compound 12-3. The reactivity of the chloro atom in the 2-position of 12-1 is significant higher compared with the chloro atom in the 3-position. Based on the known safety issue of DMSO in combination with bases like K2CO3 at high temperatures like 120 C., DMSO was substituted by N-methylpyrrolidinone (NMP). The heterogenic reaction is very water-sensitive. Traces of water led to longer reaction time and/or incomplete conversion. Longer reaction time (more than 17 h at 120 C.) or higher temperature led, due to the instability of the product 12-2, to several unknown by-products, ending up as a black tar in the reaction vessel. Therefore, it was necessary to work with water free solvent. A substantial amount of CsF was needed for this reaction. CsF is very hygroscopic and contaminated the reaction mixture with water. Therefore, to completely eliminate water from the reaction mixture, a defined amount of NMP was evaporated prior to the addition of dichloro compound 12-1 to the suspension of K2CO3 and CsF in NMP.

Reference： [1]Patent: CN104628679,2018,B .Location in patent: Paragraph 0061; 0064; 0065
[2]Patent: US2008/221327,2008,A1 .Location in patent: Page/Page column 6; 9

27
[ 110-85-0 ]
[ 89402-42-6 ]
[ 845616-81-1 ]

Yield	Reaction Conditions	Operation in experiment
99.3%	In tetrahydrofuran; at 0 - 20℃; for 1h;	EXAMPLE 4; Synthesis of 1-(3-fluoro-5-trifluoromethyl-pyridin-2-yl)-piperazine (15-1); Equipment:; A suspension of 1.0 kg piperazine (12.1 mol) in 15.0 l THF was treated at 0 C. within 30 min with a solution of 732.0 g <strong>[89402-42-6]2,3-difluoro-5-trifluoromethylpyridine</strong> 12-2, (4.0 mol) in 2.0 l THF. The reaction mixture was stirred for 30 min at 0 C. and heated to room temperature within 30 min.The white reaction mixture was extracted with 15 l water and 15 l toluene. After separation of the phases the water phase was extracted with 10 l toluene. The combined organic phase was washed twice with 10 l in total with 20 l water. The solvent of the organic phase was evaporated at 45 C. and 50 mbar to yield 984.0 g (99.3%) of 15-1 as white solid.GC analysis: 98.9 area-% of 15-1
10 g	With potassium carbonate; In tetrahydrofuran; at 20℃; for 1h;Cooling with ice;	The 2,3-5- trifluoromethylpyridine (15.0g, 0.08mmoL) and potassium carbonate (33.9g, 0.24) was dissolved in tetrahydrofuran, was added portionwise under ice-water bath and piperazine (35.2 g, 0.4mmol), then It was stirred at room temperature for 1 hour, then extracted with 40mL toluene, washed with water three times, the organic phase was dried over sodium sulfate, filtered and the solvent was evaporated to give 1- (3-fluoro-5- (trifluoromethyl) pyridin-2-yl ) piperazine (10g).

Reference： [1]Patent: US2008/221327,2008,A1 .Location in patent: Page/Page column 10
[2]Patent: CN105712928,2016,A .Location in patent: Paragraph 0094; 0095; 0096

28
[ 89402-42-6 ]
[ 100-51-6 ]
[ 431942-62-0 ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate; In N,N-dimethyl-formamide; at 20℃; for 16h;	SYNTHESIS EXAMPLE 13; Preparation of 4-[[(4,5-dihydro-5,5-dimethyl-3-isoxazolyl)sulfonyl]methyl]-3-fluoro-l- methyl-5-(trifluoromethyl)-2(lH)-pyridinone (Compound 240); Step A: Preparation of 3-fluoro-2-(phenylmethoxy)-5-(trifluoromethyl)-pyridine; To a solution of <strong>[89402-42-6]2,3-difluoro-5-trifluoromethylpyridine</strong> (4.6 g, 25.1 mmol) and benzyl alcohol (2.74 mL, 26.4 mmol) in N,Lambda/-dimethylformamide (50 mL) was added potassium carbonate (5.20 g, 37.7 mmol). The mixture was stirred for 16 h at ambient temperature and then diluted with hexanes, washed with water (2x), dried (MgSC^), filtered and concentrated. The residue was purified by column chromatography using a gradient of 100% hexanes to 3% ethyl acetate in hexanes as eluant to give the title product as a colorless oil (4.43 g).1H NMR (CDCl3) delta 8.24 (m, IH), 7.54 (dd, IH), 7.48 (d, 2H), 7.39 (t, 2H), 7.34 (t, IH), 5.52 (s, 2H).

Reference： [1]Patent: WO2009/158258,2009,A1 .Location in patent: Page/Page column 53

29
[ 1219909-66-6 ]
[ 89402-42-6 ]
[ 1219909-70-2 ]

Yield	Reaction Conditions	Operation in experiment
		To a 10 ml vial contains with (4Lambda)-4-(l-methyl-l-[3-(trifluoromethyl)phenyl]sulfonyl}ethyl)rhoirhoeridin-2-one (70 mg, 0.20 mmol) and 2 ml THF was added NaHMDS THF solution (IM, 0.21 ml, 0.21 mmol) via a syringe at - 78 0C. The resulting reaction mixture was stirred at - 78 0C for 5 min. A THF solution of 2,3-difIuoro-5- (trifluoromethyl)pyridine (40.4 mg in 0.5 ml THF, 0.22 mmol) was added via syringe. The resulting reaction mixture was allowed to warm up to room temperture and stirred for another 30 min. Volatiles were removed. Residue was diluted with water and DMF. It was purified on reverse phase column eluted with water/acetonitrile gradient solvent to give 74 mg title compound as fluffy white solid.1H-NMR (CDCl3): delta: 8.60 (s, IH), 8.19 (s, IH), 8.13 (d, J = 7.8 Hz5IH)5 7.99 (d, J = 7.7 Hz5IH)5 7.80 (t, J = 7.8 Hz, IH), 7.74 (d, J - 8.1 Hz, 2H)5 4.0 (m, IH)5 3.85 (m, IH), 2.8 (m, 3H), 2.6 (m, IH)5 2.0 (m, IH), 1.41 (s, 3H), 1.31 (s, 3H). Mass Spectra (m/e) : 513 (M+ 1 ) .

Reference： [1]Patent: WO2010/36589,2010,A1 .Location in patent: Page/Page column 40

30
[ 1228430-59-8 ]
[ 89402-42-6 ]
[ 1228430-09-8 ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate; In N,N-dimethyl-formamide; at 70℃; for 1h;	To a mixture of [((1R,4S,6R)-3-[6-methyl-3-(2-pyrimidinyl)-2-pyridinyl]carbonyl}-3-azabicyclo[4.1.0]hept-4-yl)methyl]amine D25 (50 mg) and potassium carbonate (42.7 mg, 0.309 mmol) in dry DMF (1.5 ml), a solution of <strong>[89402-42-6]2,3-difluoro-5-(trifluoromethyl)pyridine</strong> (34.0 mg, 0.186 mmol) in DMF (0.5 ml) was added and the suspension was shacken at 70 C. in a screw-capped vial for 1 hour. After cooling mixture was diluted with AcOEt and washed with water and brine. Organics were dried and evaporated, and the crude was purified by flash chromatography (KP-Sil SNAP 10 g eluting with Cy/AcOEt 1:1) affording the title compound E44 (53 mg). UPLC (Acid GEN_QC SS): rt=0.96, peak observed: 487 (M+1). C24H22F4N6O requires 486. 1H NMR (500 MHz, DMSO-d6) delta ppm 8.51-8.65 (m, 2H), 8.11 (d, 1H), 7.68 (br. s., 1H), 7.41 (d, 1H), 7.30 (br. s., 1H), 7.16-7.21 (m, 1H), 7.11 (d, 1H), 4.13 (d, 1H), 3.46-3.69 (m, 2H), 3.07-3.13 (m, 2H), 2.15 (s, 3H), 1.28-1.56 (m, 2H), 0.81 (br. s., 1H), 0.75 (d, 1H), 0.48 (d, 1H), 0.00 (d, 1H).

Reference： [1]Patent: US2010/144760,2010,A1 .Location in patent: Page/Page column 65

31
[ 1351167-99-1 ]
[ 89402-42-6 ]
[ 1351167-73-1 ]

Yield	Reaction Conditions	Operation in experiment
46%	With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃; for 18h;	Example 163(S)-3-(2,5-difluoro-4-(methylsulfonyl)phenox^'-bipiperidin\|-2-one[00579] To a solution of (S)-3-(2,5-difluoro-4-(methylsulfonyl)phenoxy)-[l,4'- bipiperidin]-2-one (Preparation G; 30 mg, 0.077 mmol) in DMF was added 2,3-difluoro-5- (trifluoromethyl)pyridine (42 mg, 0.23 mmol) and DIEA (30 L, 0.23 mmol) and the reaction was stirred at ambient temperature for 18 hours. The reaction was diluted with EtOAc and washed with brine, dried over Na2S04 and concentrated in vacuo. The residue was purified by preparative TLC (EtOAc/DCM 4: 1) to give (S)-3-(2,5-difluoro-4-(methyl- sulfonyl)phenoxy)- 1 '-(3 -fluoro-5 -(trifluoromethyl)pyridin-2-yl)- [ 1 ,4'-bipiperidin] -2-one as a white solid (20 mg, 0.035mmol, 46% yield). Mass spectrum (apci) m/z = 552.2 (M+H).

Reference： [1]Patent: WO2011/146335,2011,A1 .Location in patent: Page/Page column 139

32
[ 1415836-62-2 ]
[ 89402-42-6 ]
[ 1415835-56-1 ]

Yield	Reaction Conditions	Operation in experiment
	With N-ethyl-N,N-diisopropylamine; In 1-methyl-pyrrolidin-2-one; at 200℃; for 0.5h;Microwave irradiation;	Example 272-(2-Methyl-imidazol-1 -yl)-pyrimidine-5-carboxylic acid cvclopropyl-(3'-fluoro-5'- trifluoromethy -3,4,5,6-tetrahvdro-2H-[1 ,2'1bipyridinyl-4-yl)-amideA mixture of 2-(2-methyl-imidazol-1 -yl)-pyrimidine-5-carboxylic acid cyclopropyl- piperidin-4-yl-amide (44 mg), <strong>[89402-42-6]2,3-difluoro-5-(trifluoromethyl)pyridine</strong> (22 mg), and ethyldiisopropylamine (35 muIota_) in N-methyl-2-pyrrolidinone (1 ml_) is heated to 200C for 0.5 h in a microwave oven. The reaction mixture is concentrated and the crude product is purified by preparative HPLC (MeOH/H2O/ammonia).LC (method 16): tR = 1 .29 min; Mass spectrum (ESI+): m/z = 490 [M+H]+.
	With N-ethyl-N,N-diisopropylamine; In 1-methyl-pyrrolidin-2-one; at 200℃; for 0.5h;Microwave irradiation;	Example 27 2-(2-Methyl-imidazol-1-yl)-pyrimidine-5-carboxylic acid cyclopropyl-(3'-fluoro-5'-trifluoromethyl-3,4,5,6-tetrahydro-2H-[1,2']bipyridinyl-4-yl)-amide A mixture of 2-(2-methyl-imidazol-1-yl)-pyrimidine-5-carboxylic acid cyclopropyl-piperidin-4-yl-amide (44 mg), <strong>[89402-42-6]2,3-difluoro-5-(trifluoromethyl)pyridine</strong> (22 mg), and ethyldiisopropylamine (35 muL) in N-methyl-2-pyrrolidinone (1 mL) is heated to 200 C. for 0.5 h in a microwave oven. The reaction mixture is concentrated and the crude product is purified by preparative HPLC (MeOH/H2O/ammonia). LC (method 16): tR=1.29 min; Mass spectrum (ESI+): m/z=490 [M+H]+.

Reference： [1]Patent: WO2012/168315,2012,A1 .Location in patent: Page/Page column 128
[2]Patent: US2013/143892,2013,A1 .Location in patent: Paragraph 0501; 0502

33
N-cyclopropyl-4-oxazol-5-yl-N-piperidin-4-ylbenzamide hydrochloride [ No CAS ]
[ 89402-42-6 ]
[ 1400707-90-5 ]

Yield	Reaction Conditions	Operation in experiment
	With N-ethyl-N,N-diisopropylamine; In 1-methyl-pyrrolidin-2-one; at 120℃;	General procedure: A mixture of N-cyclopropyl-4-oxazol-5-yl-N-piperidin-4-yl-benzamide hydrogen chloride salt (52 mg), ethyldiisopropylamine (59 mg), and 2-chloro-5-ethylpyrimidine (21 mg) in N,N-dimethylformamide (1.0 mL) and 1,4-dioxane (1.5 mL) is stirred over night at 120 C. After cooling to room temperature, the solvents are evaporated and the residue is purified by HPLC (H2O/MeOH/TFA) to give the title compound. The title compound is prepared from N-cyclopropyl-4-oxazol-5-yl-N-piperidin-4-yl-benzamide hydrochloride and <strong>[89402-42-6]2,3-difluoro-5-trifluoromethyl-pyridine</strong> following a procedure analogous to that described in Example 19 using N-methylpyrrolidinone as solvent. LC (method 16): tR=0.56 min; Mass spectrum (ESI+): m/z=475 [M+H]+

Reference： [1]Patent: US2013/65906,2013,A1 .Location in patent: Paragraph 0451; 0560; 0561

34
[ 89402-42-6 ]
[ 1437801-39-2 ]

Reference： [1]Patent: WO2013/74641,2013,A1

35
[ 89402-42-6 ]
[ 1437800-70-8 ]

Reference： [1]Patent: WO2013/74641,2013,A1

36
[ 1437801-06-3 ]
[ 89402-42-6 ]
[ 1437800-30-0 ]

Yield	Reaction Conditions	Operation in experiment
16%	With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃; for 3h;	To a solution of l-(2,5-difluoro-4-(methylsulfonyl)benzyl)-3-(piperidin-4- yl)imidazolidin-2-one 2,2,2-trifluoroacetate (Intermediate 10; 0.10 g, 0.27 mmol) in DMF (2 mL) was added diisopropylethylamine (0.10 g, 0.80 mmol) and 2,3-difluoro-5- (trifluoromethyl)pyridine (0.049 g, 0.27 mmol) and the reaction was stirred at ambient temperature for 3 hours. The reaction was diluted with EtOAc (50 mL), washed with water (50 mL) and brine (50 mL), dried over MgSC^, filtered and concentrated in vacuo. The crude material was chromatographed eluting with 20% DCM/EtOAc to yield l-(2,5-difluoro-4- (methylsulfonyl)benzyl)-3 -( 1 -(3 -fluoro-5 -(trifluoromethyl)pyridin-2-yl)piperidin-4- yl)imidazolidin-2-one (0.023 g, 0.043 mmol, 16% yield). Mass spectrum 537.2 (M+H).

Reference： [1]Patent: WO2013/74641,2013,A1 .Location in patent: Paragraph 00397

37
methyl 3-fluoro-4-((2-oxo-3-(piperidin-4-yl)imidazolidin-1-yl)methyl)benzoate trifluoroacetate [ No CAS ]
[ 89402-42-6 ]
[ 1437801-38-1 ]

Yield	Reaction Conditions	Operation in experiment
38%	In N,N-dimethyl-formamide; at 20℃;	To a solution of methyl 3-fiuoro-4-((2-oxo-3-(piperidin-4- yl)imidazolidin-l-yl)methyl)benzoate 2,2,2-trifluoroacetate (Intermediate 26; 2.4 g, 5.3 mmol) in DMF (20 mL) was added <strong>[89402-42-6]2,3-difluoro-5-(trifluoromethyl)pyridine</strong> (0.98 g, 5.3 mmol) and the reaction was stirred overnight at ambient temperature. The reaction was diluted with EtOAc (200 mL) and the organic layer was washed with HC1 (100 mL) and brine (100 mL), dried over MgSC^, filtered and concentrated in vacuo. The material was purified by column chromatography using 70% EtOAc/Hexane as the eluent to yield methyl 3-fiuoro- 4-((3-(l -(3 -fiuoro-5 -(trifluoromethyl)pyridin-2-yl)piperidin-4-yl)-2-oxoimidazolidin- 1 - yl)methyl)benzoate (1.0 g, 2.0 mmol, 38% yield).

Reference： [1]Patent: WO2013/74641,2013,A1 .Location in patent: Paragraph 00415

38
[ 1259011-99-8 ]
[ 89402-42-6 ]
[ 1454291-11-2 ]

Yield	Reaction Conditions	Operation in experiment
115 mg	With potassium carbonate; In N,N-dimethyl-formamide; at 80℃; for 0.416667h;Inert atmosphere; Microwave irradiation;	Examjle 9: preparation of intermediate 9: (±)tert-butyl 4,4-difluoro-2-(((3-fluoro-5- 10 (trifluoromethyl)pyridin-2-yl)amino)methyl)piperidine-1 -carboxylateA mixture of intermediate 6 (140mg; 0.565mmo1) , 2,3-di fluoro-5-(trifluoromethyl)- pyridine (103mg; 0.565mmo1) and potassium carbonate (156mg; 1.l23mmol) in15 dry DMF(2m1) was stirred under nitrogen for 10 minutes. The reaction was performed with microwave oven: 1 cycle at 80C for 10 mm; 1 cycle at 80C for 5 mm.DMF was evaporated under reduced pressure, then the residue was taken up in NaHCO3 (sat. solution; 10 ml) and extracted with AcOEt (3x15 ml). The organic20 layers were collected, washed in with water, dried with Na2504 anhydrous and filtrated, then the solvent was evaporated under reduced pressure. Crude was purified by silica gel column (cyclohexane 100% to cyclohexane/AcOEt 90:10). Yield 11 5mg (light yellow solid).MS (ESI) m/z: 414 [M+H]+.25 1HNMR (CDCI3) 6 ppm = 8.18(s, 1H), 7.32(dd, J = 1.7, 11.0 Hz, 1H), 5.32(s, 1H),4.84(br. s., 1H), 4.21(br. s., 1H), 3.99(br. s., 1H), 3.52(d, J = 14.2 Hz, 1H), 3.17(t, J = 13.2 Hz, 1 H), 2.24 - 2.01 (m, 3H), 2.01 - 1.81 (m, 1 H), 1 .42 - 1 .33(m, 9H).
115 mg	With potassium carbonate; In N,N-dimethyl-formamide; at 80℃; for 0.416667h;Inert atmosphere; Microwave irradiation;	A mixture of intermediate 6 (140 mg; 0.565 mmol), <strong>[89402-42-6]2,3-difluoro-5-(trifluoromethyl)-pyridine</strong> (103 mg; 0.565 mmol) and potassium carbonate (156 mg; 1.123 mmol) in dry DMF (2 ml) was stirred under nitrogen for 10 minutes. The reaction was performed with microwave oven: 1 cycle at 80 C. for 10 min; 1 cycle at 80 C. for 5 min.DMF was evaporated under reduced pressure, then the residue was taken up in NaHCO3 (sat. solution; 10 ml) and extracted with AcOEt (3×15 ml). The organic layers were collected, washed in with water, dried with Na2SO4 anhydrous and filtrated, then the solvent was evaporated under reduced pressure. Crude was purified by silica gel column ( cyclohexane 100% to cyclohexane/ AcOEt 90:10). Yield 115 mg (light yellow solid). MS (ESI) m/z: 414 [M+H]+. 1HNMR (CDCl3) delta ppm=8.18 (s, 1H), 7.32 (dd, J=1.7, 11.0 Hz, 1H), 5.32 (s, 1H), 4.84 (br. s., 1H), 4.21 (br. s., 1H), 3.99 (br. s., 1H), 3.52 (d, J=14.2 Hz, 1H), 3.17 (t, J=13.2 Hz, 1H), 2.24-2.01 (m, 3H). 2.01-1.81 (m, 1H), 1.42-1.33 (m, 9H).

Reference： [1]Patent: WO2013/127913,2013,A1 .Location in patent: Page/Page column 42
[2]Patent: US2015/51226,2015,A1 .Location in patent: Paragraph 0211; 0212; 0213; 0214; 0215

39
benzyl [(2R,3S)-1-amino-3-fluoropentan-2-yl]carbamate [ No CAS ]
[ 89402-42-6 ]
benzyl [(2R,3S)-3-fluoro-1-[3-fluoro-5-(trifluoromethyl)pyridin-2-yl]amino}pentan-2-yl]carbamate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
2.95 g	With potassium carbonate; In acetonitrile; at 80℃; for 5h;	(3) Potassium carbonate was added to a solution of benzyl[(2R,3S)-1-amino-3-fluoropentan-2-yl]carbamate (2.2 g) and <strong>[89402-42-6]2,3-difluoro-5-trifluoromethylpyridine</strong> (1.74 g) in acetonitrile (45 mL), and the mixture was stirred at 80 C. for 5 hr. The reaction mixture was diluted with ethyl acetate and washed with water and brine, and then the solvent was distilled off under reduced pressure. The residue was purified by column chromatography (silica gel cartridge, hexane/ethyl acetate=95:5-20:80) to afford benzyl[[(2R,3S)-3-fluoro-1-[3-fluoro-5-(trifluoromethyl)pyridin-2-yl]amino}pentan-2-yl]carbamate (2.95 g). (ESI pos.) m/z: 418 ([M+H]+)

Reference： [1]Patent: US2013/331571,2013,A1 .Location in patent: Paragraph 0385; 0386

40
N-[(1S,2S)-2-aminocyclopentyl]-2-(2H-1,2_,3-triazol-2-yl)benzamide hydrochloride [ No CAS ]
[ 89402-42-6 ]
N-[(1S,2S)-2-[3-fluoro-5-(trifluoromethyl)pyridin-2-yl]amino}cyclopentyl]-2-(2H-1,2,3-triazol-2-yl)benzamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With N-ethyl-N,N-diisopropylamine; In dimethyl sulfoxide; at 140℃; for 1h;Microwave irradiation;	Example 105 N-[(1S,2S)-2-[3-Fluoro-5-(trifluoromethyl)pyridin-2-yl]amino}cyclopentyl]-2-(2H-1,2,3-triazol-2-yl)benzamide A solution of N-[(1S,2S)-2-aminocyclopentyl]-2-(2H-1,2,3-triazol-2-yl)benzamide hydrochloride (Intermediate 4; 100 mg, 0.33 mmol), <strong>[89402-42-6]2,3-difluoro-5-(trifluoromethyl)pyridine</strong> (CAS number 89402-42-6; 65 mg, 0.36 mmol) and DIPEA (42 mg, 0.33 mmol) in dry DMSO (1.1 ml) was subjected to microwave irradiation at 140 C. for 1 hour. The reaction was filtered through cotton wool before being purified by reverse phase preparative HPLC (eluted with acetonitrile/water containing 0.1% ammonia) to afford the title compound. 1H NMR (300 MHz, DMSO-d6) delta ppm 1.41-1.77 (m, 4H), 1.91-2.15 (m, 2H), 4.17-4.40 (m, 2H), 7.32-7.44 (m, 2H), 7.44-7.54 (m, 1H), 7.54-7.66 (m, 1H), 7.68-7.81 (m, 2H), 7.82-7.92 (m, 2H), 8.14-8.22 (m, 1H), 8.35-8.46 (m, 1H) MS ES+: 435

Reference： [1]Patent: US2015/232460,2015,A1 .Location in patent: Paragraph 1228-1231

41
N-[(1S,2S)-2-amino-4,4-difluorocyclopentyl]-2-(2H-1,2,3-triazol-2-yl)benzamide [ No CAS ]
[ 89402-42-6 ]
N-[(1S,2S)-4,4-difluoro-2-[3-fluoro-5-(trifluoromethyl)pyridin-2-yl]amino}cyclopentyl]-2-(2H-1,2,3-triazol-2-yl)benzamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With N-ethyl-N,N-diisopropylamine; In dimethyl sulfoxide; at 120℃; for 0.5h;Microwave irradiation;	Example 132 N-[(1S,2S)-4,4-Difluoro-2-[3-fluoro-5-(trifluoromethyl)pyridin-2-yl]amino}cyclopentyl]-2-(2H-1,2,3-triazol-2-yl)benzamide A microwave vial was charged with N-[(1S,2S)-2-amino-4,4-difluorocyclopentyl]-2-(2H-1,2,3-triazol-2-yl)benzamide (Intermediate 46; 50 mg, 0.15 mmol), <strong>[89402-42-6]2,3-difluoro-5-(trifluoromethyl)pyridine</strong> (CAS number 89402-42-6; 29 mg, 0.16 mmol) and DIPEA (26 mul, 0.15 mmol) in dry DMSO (485 mul). The reaction mixture was subjected to microwave irradiation at 120 C. for 30 minutes then partitioned between ethyl acetate and water. The organics were washed with water and brine, dried over sodium sulfate, filtered and concentrated in vacuo. The crude material was purified by column chromatography (silica, 0-60% ethyl acetate/petrol) to afford the title compound. 1H NMR (400 MHz, DMSO-d6) delta ppm 2.06-2.28 (m, 2H), 2.53-2.76 (m, 2H), 4.46-4.69 (m, 2H), 7.32-7.38 (m, 1H), 7.42-7.51 (m, 1H), 7.55-7.65 (m, 2H), 7.74-7.85 (m, 2H), 7.89 (s, 2H), 8.21 (s, 1H), 8.60-8.68 (m, 1H) MS ES+: 471

Reference： [1]Patent: US2015/232460,2015,A1 .Location in patent: Paragraph 1331-1334

42
[ 89402-42-6 ]
(1S,2S)-1-N-[3-fluoro-5-(trifluoromethyl)pyridin-2-yl]cyclopentane-1,2-diamine hydrochloride [ No CAS ]

Reference： [1]Patent: US2015/232460,2015,A1

43
[ 89402-42-6 ]
N-[(1S,2S)-2-[3-fluoro-5-(trifluoromethyl)pyridin-2-yl]amino}cyclopentyl]-3-(pyrimidin-2-yl)pyridine-2-carboxamide [ No CAS ]

Reference： [1]Patent: US2015/232460,2015,A1

44
[ 89402-42-6 ]
[ 586961-34-4 ]
tert-butyl N-[(1S,2S)-2-[3-fluoro-5-(trifluoromethyl)pyridin-2-yl]amino}cyclopentyl]carbamate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With N-ethyl-N,N-diisopropylamine; In dimethyl sulfoxide; at 140℃; for 5h;	Intermediate 34: (1S,2S)-1-N-[3-Fluoro-5-(trifluoromethyl)pyridin-2-yl]cyclopentane-1,2-diamine hydrochloride Step (i): tert-Butyl N-[(1S,2S)-2-[3-fluoro-5-(trifluoromethyl)pyridin-2-yl]amino}cyclopentyl]carbamate A solution of <strong>[586961-34-4]tert-butyl N-[(1S,2S)-2-aminocyclopentyl]carbamate</strong> (CAS number 586961-34-4; 2 g, 9.99 mmol), 2,3-difluoro-5-(trifluoromethyl)pyridine (CAS number 89402-42-6; 2.011 g, 10.98 mmol) and DIPEA (1.744 ml, 9.99 mmol) in DMSO (35 ml) was heated at 140 C. for 5 hours. The reaction was partitioned between ethyl acetate and water. The phases were separated and the aqueous layer was re-extracted with ethyl acetate (2×50 ml). The combined organics were washed with brine (50 ml), filtered through a hydrophobic frit and concentrated in vacuo. The crude product was purified by column chromatography (0-15% ethyl acetate/petrol) to afford the title compound. 1H NMR (400 MHz, DCM-d2) delta ppm 1.41 (s, 9H), 1.47-1.65 (m, 2H), 1.73-1.92 (m, 2H), 2.08-2.24 (m, 1H), 2.29-2.48 (m, 1H), 3.78-4.17 (m, 2H), 4.93-5.15 (m, 1H), 5.86-6.03 (m, 1H), 7.26-7.39 (m, 1H), 8.08-8.21 (m, 1H) MS ES+: 364

Reference： [1]Patent: US2015/232460,2015,A1 .Location in patent: Paragraph 0646-0649

45
(1R,2S,5R)-5-methyl-2-(propan-2-yl)cyclohexyl N-(2-amino-2-methylcyclopentyl)carbamate hydrochloride [ No CAS ]
[ 89402-42-6 ]
(1R,2S,5R)-5-methyl-2-(propan-2-yl)cyclohexyl N-(2-[3-fluoro-5-(trifluoromethyl)pyridin-2-yl]amino}-2-methylcyclopentyl)carbamate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With N-ethyl-N,N-diisopropylamine; In dimethylsulfoxide-d6; at 140℃; for 3h;Microwave irradiation;	Intermediate 28: 1-N-[3-Fluoro-5-(trifluoromethyl)pyridin-2-yl]-1-methylcyclopentane-1,2-diamine Step (i): (1R,2S,5R)-5-Methyl-2-(propan-2-yl)cyclohexyl N-(2-[3-fluoro-5-(trifluoromethyl)pyridin-2-yl]amino}-2-methylcyclopentyl)carbamate A solution of (1R,2S,5R)-5-methyl-2-(propan-2-yl)cyclohexyl N-(2-amino-2-methylcyclopentyl)carbamate hydrochloride (Intermediate 27; 1.00 g, 3.00 mmol), <strong>[89402-42-6]2,3-difluoro-5-(trifluoromethyl)pyridine</strong> (CAS number 89402-42-6; 0.412 ml, 3.30 mmol) and DIPEA (1.57 ml, 9.01 mmol) in DMSO (10 ml) was subjected to microwave irradiation at 140 C. for 3 hours. The reaction was then partitioned between ethyl acetate (10 ml) and water (10 ml), filtered through a hydrophobic frit and concentrated in vacuo. The residue was purified by column chromatography (silica, 0-12% diethyl ether petrol) to afford the title compound as a single trans-enantiomer. 1H NMR (400 MHz, DCM-d2) delta ppm 0.68-2.17 (m, 26H), 2.51-2.72 (m, 1H), 4.02-4.23 (m, 1H), 4.53-4.69 (m, 1H), 4.92 (br. s., 1H), 7.15-7.32 (m, 2H), 8.03-8.19 (m, 1H) MS ES+: 460

Reference： [1]Patent: US2015/232460,2015,A1 .Location in patent: Paragraph 0613-0616

46
[ 500556-90-1 ]
[ 89402-42-6 ]
(1S,2R,4R)-tert-butyl 2-((3-fluoro-5-(trifluoromethyl)pyridin-2-yl)amino)-7-azabicyclo[2.2.1]heptane-7-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
94%	With triethylamine; In acetonitrile; for 16h;Reflux;	11212] In a microwave vial was dissolved intermediate 13-5 (1.6 g, 7.3 mmol) mACN (11 mE). 2,3-difluoro-5-(trifluo- romethyl)pyridine (0.74 mE, 5.82 mmol) was added followed by Et3N (1 mE, 7.28 mmol). The microwave vial was capped and the reaction mixture was heated to reflux for 16 h. Solvent was evaporated and purification via silica gel chromatography (0-20% EtOAc in hexanes) gave the title compound (1.7 g, 94%). MS (ESI): mass calcd. for C,7H2,F4N302, 375.2; mlz found, 376.2 [M+H]. ?H NMR (500 MHz, CDC13): oe 8.15 (s, 1H), 7.29 (dd, J=10.8, 2.0 Hz, 1H), 5.23 (s, 1H),4.36-4.27 (m, 1H), 4.27-4.21 (m, 1H), 4.21-4.15 (m, 1H),2.08 (dd, J=13.1, 7.7 Hz, 1H), 1.91-1.80 (m, 1H), 1.80-1.70 (m, 1H), 1.63-1.48 (m, 2H), 1.43 (s, 1OH).

Reference： [1]Patent: US2016/46640,2016,A1 .Location in patent: Paragraph 1212
[2]ACS Medicinal Chemistry Letters,2020

47
4-hydroxy-3-(piperidin-4-yl)-4-(trifluoromethyl)-1,4,5,7-tetrahydro-6H-pyrazolo[3,4-b]pyridine-6-one hydrochloride [ No CAS ]
[ 89402-42-6 ]
3-{1-[3-fluoro-5-(trifluoromethyl)pyridin-2-yl]piperidin-4-yl}-4-hydroxy-4-(trifluoromethyl)-1,4,5,7-tetrahydro-6H-pyrazolo[3,4-b]pyridine-6-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
44%	With 1,8-diazabicyclo[5.4.0]undec-7-ene; N-ethyl-N,N-diisopropylamine; In dimethyl sulfoxide; at 60℃; for 0.333333h;Microwave irradiation;	4-hydroxy was prepared in Reference Example 60 3- (piperidin-4-yl) -4- (trifluoromethyl) -1,4,5,7- tetrahydro -6H- pyrazolo [3,4-b] pyridin-6-one hydrochloride (150mg, 0.440mmol) in dimethyl sulfoxide (0.5 mL) solution of, N, N- diisopropylethylamine (89.8muL, 0.528mmol), and 6-fluoro-3- ( the compounds described in trifluoromethyl) pyridine-2-carbonitrile (US2008 / 275057 pamphlet, 136mg, 0.660mmol) was added, using a Biotage Inc. the Initiator (TM), 60 C., 20 min micro and the mixture was stirred while irradiating the waves.The reaction mixture was poured into water, and extracted twice with ethyl acetate, the resulting organic layer was washed successively with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure.The resulting residue was purified by silica gel column chromatography was purified in the elution solvent hexane / ethyl acetate = 88 / 12-0 / 10 gradient)], the title compound (43.1mg, yield: 21%) a. Instead of 6-chloro-4- (trifluoromethyl) pyridine-3-carbonitrile, using 2,3-difluoro-5- (trifluoromethyl) pyridine (121 mg, 0.66 mmol), in Example 95 the reaction was carried out in the same manner as described method, the title compound (90mg, yield: 44%) was obtained.

Reference： [1]Patent: JP2015/113323,2015,A .Location in patent: Paragraph 0727 - 0729; 0730 - 0732; 0733 - 0735

48
(2S,3R)-benzyl 2-(aminomethyl)-5,5-difluoro-3-methylpiperidine-1-carboxylate [ No CAS ]
[ 89402-42-6 ]
(2S,3R)-benzyl 5,5-difluoro-2-(((3-fluoro-5-(trifluoromethyl)pyridin-2-yl)amino)methyl)-3-methylpiperidine-1-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With caesium carbonate; In N,N-dimethyl-formamide; at 20℃; for 2h;	To a mixture of (2S,3R)-benzyl 2-(aminomethyl)-5,5-difluoro-3-methylpiperidine-1-carboxylate (1eq) and Cs2CO3 (2eq) in DMF (20mL) was added <strong>[89402-42-6]2,3-difluoro-5-(trifluoromethyl)pyridine</strong> (3eq). The reaction was stirred at room temperature for 2h wherein the starting material was judged consumed as indicated by reverse-phase analytical HPLC. The reaction was cooled, and diluted with EtOAc, and water. The layers were separated, and the organic phase was washed with water (3x), brine, dried (MgSO4) and concentrated. The crude residue was purified by chromatography on SiO2 (EtOAc/hex) to give the title compound as a near colorless oil which solidified. ESI-MS (m/z): 462.2 [M+1]+.

Reference： [1]Patent: WO2017/139603,2017,A1 .Location in patent: Page/Page column 159

49
1-{5-methanesulfonyl-2-[(1S)-2,2,2-trifluoro-1-methylethoxy]benzoyl}piperazine [ No CAS ]
[ 89402-42-6 ]
[ 845614-11-1 ]

Yield	Reaction Conditions	Operation in experiment
28 g	With potassium carbonate; In acetonitrile; for 4h;Reflux;	The above oil, 11 g of <strong>[89402-42-6]2,3-difluoro-5-trifluoromethylpyridine</strong>, 16 g of potassium carbonate and 350 ml of acetonitrile were added to a 1000 ml reaction flask, stirred, and heated under reflux for 4 hours. Cool and filter. The filtrate was concentrated to dryness to give a yellow oil which was recrystallized from ethanol to give 28 g of a white solid, which was the target product, Bitopertin. The total yield was 80.4%.

Reference： [1]Patent: CN104628679,2018,B .Location in patent: Paragraph 0101; 0105

50
[ 89402-42-6 ]
[ 1202473-98-0 ]

Reference： [1]Patent: WO2009/158258,2009,A1

51
[ 89402-42-6 ]
[ 1202474-00-7 ]

Reference： [1]Patent: WO2009/158258,2009,A1

52
[ 89402-42-6 ]
[ 1202473-99-1 ]

Reference： [1]Patent: WO2009/158258,2009,A1

53
[ 89402-42-6 ]
[ 1202474-02-9 ]

Reference： [1]Patent: WO2009/158258,2009,A1

54
[ 89402-42-6 ]
[ 1202474-03-0 ]

Reference： [1]Patent: WO2009/158258,2009,A1

55
[ 89402-42-6 ]
[ 1202473-65-1 ]

Reference： [1]Patent: WO2009/158258,2009,A1

56
[ 89402-42-6 ]
[ 1202474-01-8 ]

Reference： [1]Patent: WO2009/158258,2009,A1

57
2-(2,6-diethylphenyl)-3-(5-fluoro-7-methoxy-1H-indol-4-yl)-4,5,6,7-tetrahydropyrazolo[4,3-c]pyridine hydrochloride [ No CAS ]
[ 89402-42-6 ]
2-(2,6-diethylphenyl)-3-(5-fluoro-7-methoxy-1H-indol-4-yl)-5-[3-fluoro-5-(trifluoromethyl)-2-pyridyl]-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With triethylamine; In acetonitrile; at 80℃; for 0.5h;	[0237] Triethylamine (0.12 mL, 0.86 mmol) was added to a suspension of 2-(2,6- diethylphenyl)-3-(5-fluoro-7-methoxy-1H-indol-4-yl)-4,5,6,7-tetrahydropyrazolo[4,3-c]pyridine hydrochloride (13 mg, 0.023 mmol) and <strong>[89402-42-6]2,3-difluoro-5-(trifluoromethyl)pyridine</strong> (50 mg, 0.29 mmol) in MeCN (1.5 mL). The resulting mixture was stirred at 80 C for 0.5 h. After cooling to room temperature, the reaction mixture was diluted with EtOAc, washed with aqueous NaHCO3 and dried over Na2SO4. The solvent was removed under reduced pressure and the residue was purified by silica gel flash chromatography (0 to 45% EtOAc in hexanes) to afford 2-(2,6- diethylphenyl)-3-(5-fluoro-7-methoxy-1H-indol-4-yl)-5-[3-fluoro-5-(trifluoromethyl)-2-pyridyl]- 6,7-dihydro-4H-pyrazolo[4,3-c]pyridine . 1H NMR (400 MHz, CDCl3) 8.44 (br s, 1H), 8.17 (d, J = 0.8 Hz, 1H), 7.38 (dd, J = 13.2 Hz, 1.6, 1H), 7.12-7.22 (m, 3H), 6.88 (d, J = 7.6 Hz, 1H), 6.34 (t, J = 2.6 Hz, 1H), 6.27 (d, J = 11.6 Hz, 1H), 4.73 (d, J = 16 Hz, 1H), 4.46 (d, J = 16 Hz, 1H), 4.06 (m, 2H), 3.87 (s, 3H), 3.11 (t, J = 5.6 Hz, 2H), 2.52 (sextet, J = 7.6 Hz, 1H), 2.43 (sextet, J = 7.5 Hz, 1H), 2.17 (sextet, J = 7.6 Hz, 1H), 1.96 (sextet, J = 7.5 Hz, 1H), 1.24 (t, J = 7.6 Hz, 3H), 0.75 (t, J = 7.6 Hz, 3H). MS: (ES) m/z calculated for C31H29F5N5O [M + H]+ 582.2, found 582.2.

Reference： [1]Patent: WO2018/222598,2018,A1 .Location in patent: Paragraph 0237

58
2-(2,6-diethylphenyl)-3-(6-fluoro-7-methoxy-1H-indazol-4-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine hydrochloride [ No CAS ]
[ 89402-42-6 ]
2-(2,6-diethylphenyl)-5-(3-fluoro-5-(trifluoromethyl)pyridin-2-yl)-3-(6-fluoro-7-methoxy-1H-indazol-4-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With lithium carbonate; N-ethyl-N,N-diisopropylamine; at 65℃; for 2h;	[0246] N,N-diisopropylethylamine (0.1 mL, 0.58 mmol) was added to a suspension of 2-(2,6- diethylphenyl)-3-(6-fluoro-7-methoxy-1H-indazol-4-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3- c]pyridine hydrochloride (30 mg, 0.07 mmol), <strong>[89402-42-6]2,3-difluoro-5-(trifluoromethyl)pyridine</strong> (15 mg, 0.08 mmol), and Li2CO3 (20 mg, 0.27 mmol) in DMSO (10 mL) under magnetic stirring. The resulting mixture was stirred at 65 C for 2 h. After cooling to room temperature, the reaction mixture was diluted with EtOAc, washed with brine and dried over MgSO4. The solvent was removed under reduced pressure and the residue was purified by Preparative TLC (40% EtOAc in hexanes) followed by trituration in MeOH to afford 2-(2,6-diethylphenyl)-5-(3-fluoro-5- (trifluoromethyl)pyridin-2-yl)-3-(6-fluoro-7-methoxy-1H-indazol-4-yl)-4,5,6,7-tetrahydro-2H- pyrazolo[4,3-c]pyridine .1H NMR (400 MHz, CDCl3) 10.30 (s, 1H), 8.22 (dd, J = 1.2, 2.3 Hz, 1H), 8.00 (s, 1H), 7.41 (dd, J = 2.0, 13.2 Hz, 1H), 7.18 7.30 (m, 1H), 7.07 (d, J = 7.7 Hz, 2H), 6.46 (d, J = 13.1Hz, 1H), 4.67 (s, 2H), 4.13 (s, 3H), 4.08 (t, J = 5.9 Hz, 2H), 3.10 (t, J = 5.9 Hz, 2H), 2.13 2.36 (m, 4H), 1.02 (t, J = 8.0 Hz, 6H). MS: (ES) m/z calculated C30H28F5N6O [M + H]+ 583.2, found 583.2.

Reference： [1]Patent: WO2018/222598,2018,A1 .Location in patent: Paragraph 0246; 0245

59
3-bromo-2-(2,6-dimethylphenyl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine hydrochloride [ No CAS ]
[ 89402-42-6 ]
3-bromo-2-(2,6-dimethylphenyl)-5-(3-fluoro-5-(trifluoromethyl)pyridin-2-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate; N-ethyl-N,N-diisopropylamine; In acetonitrile; at 85℃; for 2h;	[0283] N,N-diisopropylethylamine (0.2 mL, 1.15 mmol) was added to a suspension of 3- bromo-2-(2,6-dimethylphenyl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine hydrochloride (1 g, 2.9 mmol), <strong>[89402-42-6]2,3-difluoro-5-(trifluoromethyl)pyridine</strong> (1.1 g, 6 mmol), and K2CO3 (1.38 g, 10 mmol) in MeCN (10 mL) under magnetic stirring. The resulting mixture was stirred at 85 C for 2 h. After cooling to room temperature, the reaction mixture was diluted with EtOAc, washed with brine and dried over MgSO4. The solvent was removed under reduced pressure and the residue was purified by silica gel flash chromatography (2 to 15% EtOAc in hexanes) to afford 3-bromo-2-(2,6-dimethylphenyl)-5-(3-fluoro-5-(trifluoromethyl)pyridin-2-yl)-4,5,6,7-tetrahydro- 2H-pyrazolo[4,3-c]pyridine . MS: (ES) m/z calculated for C20H17BrF4N4 [M + H]+ 469.1, found 469.1.

Reference： [1]Patent: WO2018/222598,2018,A1 .Location in patent: Paragraph 0283

60
C₂₃H₂₃FN₄*ClH [ No CAS ]
[ 89402-42-6 ]
C₂₉H₂₄F₅N₅ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With N-ethyl-N,N-diisopropylamine; In acetonitrile; at 80℃; for 4h;	[0293] N,N-diisopropylethylamine (0.040 mL, 0.23 mmol) was added to a suspension of 3-(5- fluoro-7-methyl-1H-indazol-4-yl)-2(2,6-dimethylphenyl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3- c]pyridine hydrochloride (48 mg, 0.12 mmol) and <strong>[89402-42-6]2,3-difluoro-5-(trifluoromethyl)pyridine</strong> (94 mg, 0.51 mmol) in acetonitrile (1 mL) under magnetic stirring. The resulting mixture was stirred at 80 C for 4 h. The solvent was removed in vacuo and the residue was purified by silica gel flash chromatography (0 to 60% MTBE in hexanes) followed by trituration with MTBE in hexanes to obtain 3-(5-fluoro-7-methyl-1H-indazol-4-yl)-2-(2,6-dimethylphenyl)-5-(2-fluoro-5- (trifluoromethyl)pyridin-2-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine . 1H NMR (400 MHz, CD3OD) 8.21 (s, 1H), 7.63 (dd, J = 1.9, 13 Hz, 1H), 7.10 (d, J = 4.8 Hz, 2H), 6.84 (t, J = 4.8 Hz, 1H), 6.57 (d, J = 12 Hz, 1H), 6.32 (d, J = 2.9 Hz, 1H), 4.78 (d, J = 16 Hz, 1H), 4.40 (d, J = 16 Hz, 1H), 4.10 (t, J = 5.6 Hz, 2H), 3.07 (t, J = 5.6 Hz, 2H), 2.47 (s, 3H), 2.18 (s, 3H), 1.70 (s, 3H). MS: (ES) m/z calculated for C29H25F5N5 [M + H]+ 538.2, found 538.2.

Reference： [1]Patent: WO2018/222598,2018,A1 .Location in patent: Paragraph 0293

61
[ 89402-42-6 ]
3-(7-chloro-3-methyl-1H-indol-4-yl)-2-(2,6-diethylphenyl)-5-(3-fluoro-5-(trifluoromethyl)pyridin-2-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine [ No CAS ]